The long-range goal of our research is to understand the structural basis of gene regulation and how repressors, activators, and anti-terminators regulate transcription. Over the years, we have focused on the two paradigms, the lactose operon of E-coli and the "genetic switch" of bacteriophage lambda. This grant originally funded the three-dimensional structure determination of the intact lac repressor, the lac repressor bound to the gratuitous inducer 1-isopropyl-D-thiogalactoside (IPTG) and the lac repressor complexed with a 21 base-pair symmetric operator DNA. These three structures have provided a detailed structural model for repressor in the induced and the repressed states, and a framework for understanding a wealth of biochemical and genetic information (Lewis et al., 1996). Building upon these results, we designed new experiments and solved structures to probe more deeply the function of this protein. In this last granting period, we also resumed earlier studies of the repressor from phage lambda (Bell et al., 2000) and provided structural insight as to the molecular basis of this genetic switch. In this funding period, we plan to continue our studies on proteins that regulate transcription. The long-range goal of our research is to understand the structural basis of gene regulation and how repressors, activators, and anti-terminators regulate transcription.